FOXO3a Activation by HDAC Class IIa Inhibition Induces Cell Cycle Arrest in Pancreatic Cancer Cells

• Published in: Pancreas Vol. 49; no. 1; p. 135
• Main Authors: Usami, Makoto, Kikuchi, Shohei, Takada, Kohichi, Ono, Michihiro, Sugama, Yusuke, Arihara, Yohei, Hayasaka, Naotaka, Nakamura, Hajime, Ikeda, Yuuki, Hirakawa, Masahiro, Yoshida, Makoto, Miyanishi, Koji, Kobune, Masayoshi, Kato, Junji
• Format: Journal Article
• Language: English
• Published: United States 01.01.2020
• Subjects: Cell Line, Tumor; Cell Proliferation - drug effects; Cell Proliferation - genetics; Drug Synergism; Forkhead Box Protein O3 - genetics; Forkhead Box Protein O3 - metabolism; G1 Phase Cell Cycle Checkpoints - drug effects; G1 Phase Cell Cycle Checkpoints - genetics; Gene Expression Profiling - methods; Gene Expression Regulation, Neoplastic - drug effects; Histone Deacetylase Inhibitors - pharmacology; Histone Deacetylases - genetics; Histone Deacetylases - metabolism; Humans; Oligopeptides - pharmacology; Pancreatic Neoplasms - genetics; Pancreatic Neoplasms - metabolism; Pancreatic Neoplasms - pathology; Phosphatidylinositol 3-Kinases - metabolism; Proteasome Inhibitors - pharmacology; Proto-Oncogene Proteins c-akt - metabolism; Signal Transduction - drug effects
• DOI: 10.1097/MPA.0000000000001462

Pancreatic cancer (PC) is highly aggressive with multiple oncogenic mutations. The efficacy of current chemotherapy is poor, and new therapeutic targets are needed. The forkhead box (FOX) proteins are multidirectional transcriptional factors strongly implicated in malignancies. Their expression is consistently suppressed by several oncogenic pathways such as PI3K/AKT signaling activated in PC. A recent study showed that class IIa histone deacetylases (HDAC) can act as a transcriptional suppressor. In this study, we hypothesized that HDAC class IIa inhibition would upregulate FOXO3a expression, thereby inducing its transcription-dependent antitumor effects. We confirmed the change of FOXO3a expression and the effect of the cell growth inhibition by HDAC class IIa inhibition in AsPC-1 cells. Because FOXO3a is subject to ubiquitylation-mediated proteasome degradation, we examined the synergistic activation of FOXO3a by HDAC class IIa selective inhibitor TMP269 combined with proteasome inhibitor carfilzomib. We observed that TMP269 induced FOXO3a expression in a dose-dependent manner and inhibited cell growth in AsPC-1 cells. G1/S arrest was observed. FOXO3a expression was further increased and cell growth inhibition was dramatically enhanced by TMP269 combined with carfilzomib. Dual inhibition of class IIa HDACs and proteasome could be a promising new strategy for modifying FOXO3a activity against PC.